HIV/AIDS is a global pandemic with 34 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the successful results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda, with a report efficacy of 51%. Five years after the trial was completed, overall HIV incidence in Rakai was 0.50/100 person-years in circumcised men and 1.93/100 person-years in uncircumcised men for an adjusted effectiveness of 73%. There were no significant differences in sociodemographic characteristics and sexual behaviors between controls accepting male circumcision and those remaining uncircumcised. It is therefore evident that male circumcision results in high community effectiveness for HIV prevention and remains a very important intervention in controlling HIV. We have also shown that among HIV-negative men in the above trial, male circumcision decreases high-risk human papillomavirus (HR-HPV) prevalence. Since HR-HPV varies by anatomic site, we evaluated HR-HPV at multiple locations. We found that although HR-HPV was more frequently detected on the coronal sulcus than penile shaft, male circumcision reduced HR-HPV prevalence at both sites. The reduced HR-HPV prevalence by male circumcision is due to decreased incidence and increased clearance. In addition, male circumcision reduced HR-HPV prevalence and the incidence of multiple HR-HPV infections in HIV-positive men. The reduced acquisition and increased clearance of HR-HPV among circumcised men likely has benefits for female partners. Among female partners of circumcised men in a randomized controlled trial, we found that circumcision of HIV-negative men reduces HR-HPV prevalence by 28%, reduces HR-HPV incidence and increases HR-HPV clearance in female partners. However, contrary to findings in HIV-uninfected men, male circumcision of HIV-infected men did not affect HR-HPV transmission to female partners. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about HPV infection among heterosexual men. The burden of HPV infection is high with prevalence at 90.7% among HIV-positive men and 60.9% among HIV-negative men. HR-HPV incidence is also twice as common among the HIV-infected men. HR-HPV incidence was higher in the unmarried and decreased with age. In addition, the association between HPV infection and HIV seroconversion risk is unclear and the genital cellular immunology has not been evaluated. Thus, we conducted a case-control analysis nested within a male circumcision trial and found that HPV clearance was associated with subsequent HIV seroconversion. HPV infection was associated with increased epidermal dendritic cell density that potentially mediates HIV seroconversion. Accurate methods to estimate HIV incidence are needed to monitor the leading edge of the epidemic, identify groups at high risk of infection, and evaluate the effectiveness of prevention interventions. Biomarker-based methods that identify recently infected persons in cross-sectional samples are a promising alternative approach for estimating HIV incidence. We determined that the BED capture immunoassay (BED-CEIA), the current assay that is used to estimate the number of new infections in the US was associated with multiple source of misclassification including: viral suppression, AIDS, and race. We developed a multi-assay algorithm (MAA) for estimating cross-sectional HIV incidence that includes the BED-CEIA, an antibody avidity assay, HIV viral load, and CD4 cell count. We analyzed 1,782 samples from 709 individuals in the US with known duration of HIV infection. We compared annual incidence estimated with the MAA to annual incidence based on HIV seroconversion in a longitudinal cohort. In comparison with the HIVNET001 cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI: 0.70%-1.55%) while the incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI: 0.51%-1.71%). We did a similar analysis on the end of trial visit for HPTN064 and again observed similar estimates between what was estimated by our multi-assay algorithm 0.13% (95% CI: 0.010.76%) and what was observed longitudinally 0.24% (95% CI: 0.070.62%). Further evaluations are underway with non-clade B subtypes. HIV superinfection has been described in a number of populations but its frequency and its clinical relevance remains unknown. We designed and tested a next generation sequencing protocol to identify HIV superinfection by targeting two regions of the HIV viral genome, p24 and gp41. Mixing control samples infected with HIV subtypes A or D at different ratios to determine the inter- and intra-subtype sensitivity validated the method. This amplicon-based protocol was able to consistently identify distinct inter-subtype strains at ratios of 1%, and intra-subtype variants at 5%. Using this novel next-generation ultradeep sequencing technique, we found that the rate of superinfection was 1.44 superinfections per 100 person years. This was compared to primary HIV incidence in 20,220 initially HIV-negative individuals in the general population in same region of Uganda (1.15 new HIV infections per 100py). These two rates were not significantly different indicating that HIV superinfection occurs at a similar rate to primary HIV infection. These finding suggest that superinfection is a relatively frequent event has substantial implications for HIV prevention, clinical management and future vaccine development. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.